MS Abstracts 04b-2g1

Objective
To emphasize the diagnostic importance of change in the Headache pattern which pointed to Cerebral Venous Thrombosis in two patients after Lumbar Puncture and high-dose IntraVenous MethylPrednisolone for suspected Multiple Sclerosis.

Results
Both patients had a diagnostic Lumbar Puncture for suspected Multiple Sclerosis and were treated with high-dose IntraVenous MethylPrednisolone.

Both developed a PostLumbar Puncture Headache that was initially Postural, typical of low CerebroSpinal Fluid pressure.

Three days later, the Headache became constant, lost its Postural component, and was associated with Bilateral Papilledema. Magnetic Resonance Imaging of the Brain disclosed Superior Sagittal and Lateral Sinuses Thrombosis.

The diagnostic difficulties of such cases and the potential role of Lumbar Puncture and CorticoSteroids as risk factors for Cerebral Venous Thrombosis are discussed.

Conclusions
When a typical Postdural Puncture Headache loses its Postural component, investigations should be performed to rule out Cerebral Venous Thrombosis, particularly in the presence of other risk factors.

Objective
To compare the recently developed Guy's Neurologic Disability Scale (GNDS), based on patient self-report, with both Neurologist rating of Neurologic Examination abnormalities.

Using the Expanded Disability Status Scale (EDSS) and observations of functional impairment on the Multiple Sclerosis Functional Composite (MSFC) in the assessment of disease impact in MS.

Methods
Two hundred ninety MS patients were recruited at an outpatient clinic. Impairment and Disability were assessed using GNDS, EDSS, and MSFC.

Correlations between GNDS, EDSS, MSFC, and their corresponding components were studied for the total population, MS phenotypes, and three disability strata.

Results
Mean scores were 4.6 (SD, 2.0) for EDSS, 0.0 (SD, 0.8) for MSFC, and 14.6 (SD, 7.9) for GNDS.

Good correlations were found between GNDS and EDSS (r = 0.73), between GNDS and MSFC (r = -0.68), and between different subcategories of the GNDS and EDSS, MSFC, and their corresponding components.

Remarkably good correlations were found between lower limb function and all three scales. Poor correlations were also found, especially between different measurements focusing on Cognitive function.

Conclusion
The good correlations between GNDS and both EDSS and MSFC were mainly due to the importance of Spinal Cord-related Neurologic functions in all three scoring systems.

A marked discrepancy was found for the assessment of Cognition between objective measurements and subjective complaints.

Because patients' self-reporting correlates well with results of physical examination, GNDS can offer a valuable way to measure disease impact in MS. However, GNDS is not an adequate screen of Cognitive Dysfunction.

Purpose
To report a patient with Multiple Sclerosis and associated with Granulomatous Uveitis, and how AntiLipoArabinoMannan (LAM)-B AntiBody can play a key role in differential diagnosis.

Methods
Case report.

Results
A 35-year-old Japanese woman with Multiple Sclerosis, diagnosed 3 years ago, presented with blurred vision in her left eye.

Ophthalmological examinations revealed Granulomatous Iridocyclitis in her left eye and Retinal Periphlebitis in both eyes.

The diagnosis of Tuberculosis was suspected because of a positive Tuberculin skin test. However, a further examination by an anti-LAM-B AntiBody test excluded active Tuberculosis.

Her clinical findings were thought most likely to be caused by Multiple Sclerosis and treated with CorticoSteroids.

Conclusion
We should consider the possibility of Multiple Sclerosis as the underlying origin in patients with Granulomatous Uveitis.

A measurement of anti-LAM-B AntiBody titer may be useful in the differential diagnosis of Granulomatous Uveitis.

T-Cells that recognize particular self Ags are thought to be important in the PathoGenesis of AutoImmune Diseases. In Multiple Sclerosis, susceptibility is associated with HLA-DR2, which can present Myelin-derived peptides to CD4⁺ T-Cells.

To generate molecules that target such T-Cells based on the specificity of their TCR, we expressed a soluble dimeric DR2-IgG fusion protein with a bound peptide from Myelin Basic Protein (MBP).

Soluble, dimeric DR2/MBP Peptide complexes activated MBP-specific T-Cells in the absence of signals from costimulatory or Adhesion Molecules.

This initial signaling through the TCR rendered the T-Cells unresponsive (Anergic) to subsequent activation by peptide-pulsed APCs.

Fluorescent labeling demonstrated that anergic T-Cells were initially viable, but became susceptible to late Apoptosis due to insufficient production of Cytokines.

Dimerization of the TCR with bivalent MHC Class II/Peptide complexes therefore allows the induction of anergy in human CD4⁺ T-Cells with a defined MHC/Peptide specificity.

Tumor Necrosis Factor-alpha (TNF-) and InterLeukin-1beta (IL-1ß), essential components in the PathoGenesis of ImmunoInflammatory Diseases, are strongly induced in Monocytes by direct contact with stimulated T-Lymphocytes.

This study demonstrates that adult Human Serum (HS) but not fetal calf or Cord blood Serum displays inhibitory activity toward the contact-mediated activation of Monocytes by stimulated T-Cells, decreasing the production of both TNF- and IL-1ß.

Fractionation of HS and N-terminal MicroSequencing as well as Electroelution of material subjected to preparative Electrophoresis revealed that ApoLipoProtein A-I (apo A-I), a "negative" acute-phase protein, was the inhibitory factor.

Functional assays and flow cytometry analyzes show that high-density LipoProtein (HDL)-associated Apo A-I inhibits contact-mediated activation of Monocytes by binding to stimulated T-Cells, thus inhibiting TNF- and IL-1ß production at both protein and messenger RNA levels.

Furthermore, apo A-I inhibits Monocyte inflammatory functions in peripheral blood MonoNuclear Cells activated by either specific Antigens or Lectins without affecting cell proliferation.

These results demonstrate a new anti-inflammatory activity of HDL-associated apo A-I that might have modulating functions in nonseptic conditions.

Therefore, because HDL has been shown to bind and neutralize LipoPolySaccharide, HDL appears to play an important part in modulating both acute and chronic inflammation.

The novel anti-inflammatory function of Apo A-I reported here might lead to new therapeutic approaches in inflammatory diseases such as Rheumatoid Arthritis, Multiple Sclerosis, Systemic Lupus Erythematosus, and AtheroSclerosis.

Background And Purpose
Contrast enhancement on MR images of patients with Multiple Sclerosis (MS) is known to be associated with abnormalities of the Blood-Brain Barrier (BBB).

However, little is known about diagnostic patterns and common features of enhanced MS lesions. This study was designed to evaluate initial enhancement patterns, changes in these enhancing patterns, and duration of enhancement in a cohort of patients with MS.

Methods
Twenty-five patients with Clinically Definite MS were studied retrospectively. The appearance of enhancing lesions and sequential changes in the appearance on Axial contrast-enhanced Spin-Echo images were evaluated.

The enhancing lesions were classified as Nodular, Ringlike, or "other" (eg, Arclike).

Results
Of 301 new enhancing lesions, 205 (68%) showed Nodular enhancement, 70 (23%) a Ring pattern, and 26 (9%) a pattern neither Nodular nor Ringlike (eg, Arclike).

Two hundred eighty (93%) of 301 enhancing lesions disappeared within 6 months, and seven (2%) lesions showed persistent enhancement longer than 6 months.

The other 14 (5%) lesions, which disappeared by the time of the next scan, were excluded, because the course between two examinations was longer than 6 months.

Of nine persisting Nodular enhancing lesions on the follow-up images, seven were decreased in size, whereas all of two persisting Ringlike enhancing lesions on the follow-up images were larger than before.

Conclusion
Nodular enhancement is the predominant enhancement pattern for new MS lesions, and the temporal course of enhancement is usually shorter than 6 months.

The appreciation of the evolution of MS-enhanced lesions aids in both identifying new MS lesions and distinguishing these lesions from other pathologic entities. This may be helpful in clinically evaluating the stage of MS Lesions.

The aim of the study was to investigate whether impaired control of transmission in Spinal Inhibitory Pathways contributes to the functional disability of patients with Spasticity.

To this end, transmission in the pathways mediating DiSynaptic Reciprocal Ia Inhibition and PreSynaptic Inhibition was investigated in 23 healthy subjects and 20 patients with Spastic Multiple Sclerosis during ankle DorsiFlexion and Plantar Flexion.

In healthy subjects, but not in Spastic patients, the Soleus H reflex was depressed at the onset of DorsiFlexion (300 ms rise time, 20% of maximal voluntary effort).

At the onset of Plantar Flexion, the Soleus H reflex was more facilitated in the healthy subjects than in the patients.

The H reflex increased more with increasing level of tonic Plantar Flexion and decreased more with DorsiFlexion in the healthy subjects than in the Spastic patients.

Transmission in the DiSynaptic Ia Reciprocal Inhibition pathway from ankle DorsiFlexors to Plantar Flexors was investigated by conditioning the Soleus H reflex by previous stimulation of the common peroneal nerve (conditioning-test interval 2-3 ms; stimulation intensity 1.05 times the motor response threshold).

At the onset of DorsiFlexion, stimulation of the common Peroneal Nerve evoked a significantly larger Inhibition than at rest in the healthy subjects but not in the Spastic patients.

At the onset of Plantar Flexion the Inhibition decreased in the healthy subjects, but because only weak Inhibition was observed at rest in the patients it was not possible to determine whether a similar decrease occurred in this group.

There were no differences in the modulation of Inhibition during tonic Plantar Flexion and DorsiFlexion in the two populations.

Presynaptic Inhibition of Ia afferents terminating on Soleus Motor Neurons was evaluated from the MonoSynaptic Ia facilitation of the Soleus H reflex evoked by Femoral Nerve stimulation.

Femoral Nerve facilitation was decreased at the onset of DorsiFlexion and increased at the onset of Plantar Flexion in the healthy subjects and patients, but the changes were significantly greater in the healthy subjects.

There was no difference between the two populations in the modulation of PreSynaptic Inhibition during tonic Plantar Flexion and DorsiFlexion.

It is suggested that the abnormal regulation of DiSynaptic Reciprocal Inhibition and PreSynaptic Inhibition in patients with Spasticity is responsible for the abnormal modulation of stretch reflexes in relation to voluntary movement in these patients.

Lack of an increase in Reciprocal Inhibition and PreSynaptic Inhibition at the onset of DorsiFlexion may be responsible for the tendency to elicitation of unwanted stretch reflex activity and co-contraction of antagonistic muscles in patients with Spasticity.

Monocytes can differentiate into Dendritic Cells (DC), cells with a pivotal role in both protective Immunity and Tolerance. Defects in the maturation or function of DC may be important in the development of AutoImmune Disease.

We sought to establish if there were differences in the Cytokine (Granulocyte-Macrophage Colony-Stimulating Factor and IL-4)-driven maturation of Monocytes to DC in patients with MS and whether drugs used to treat MS affected this process in vitro.

We have demonstrated that there is no defect in the ability of Magnetic Activated Cell Sorting (MACS)-purified Monocytes from patients with MS to differentiate to DC.

But equally they show no tendency to acquire a DC phenotype without exogenous Cytokines.

Interferon-beta-1a prevents the acquisition of a full DC phenotype as determined by light and electron microscopy and by flow cytometry.

MethylPrednisolone not only prevents the development of Monocyte-derived DC but totally redirects Monocyte differentiation towards a Macrophage phenotype.

Evidence is evolving for a role for DC in Central Nervous System Immunity, either within the Brain or in Cervical Lymph Nodes. The demonstrated effect of both drugs on Monocyte differentiation may represent an important site for Immune therapy in MS.

Neuronal damage and loss is likely to underlie irreversible disability in Multiple Sclerosis (MS). The time of onset, location and extent of Neuronal damage in early disease are all uncertain.

To explore this issue 16 patients with short duration, mild Relapsing/Remitting disease (mean disease duration 1.8 years, median EDSS 1) were studied.

Using short echo time Proton Magnetic Resonance Spectroscopic Imaging (1H-MRSI) to quantify the concentration of the Neuronal marker N-AcetylAspartate (NAA).

The data were compared with those from 12 age-matched controls. 1H-MRSI was obtained from a 1.5-cm-thick slice just above the Lateral Ventricles.

The Linear Combination (LC) Model combined with locally developed software allowed automated measurement of absolute metabolite concentrations from lesions, Normal-Appearing White Matter (NAWM) and Cortical Gray Matter (CGM).

MS CGM exhibited significantly lower NAA (P = 0.01) and Myo-Inositol (P = 0.04) than control CGM.

MS NAWM exhibited a lower concentration of NAA (P = 0.01) and increased Myo-Inositol (P = 0.03) than control White Matter. More marked reductions in NAA and increases in Myo-Inositol were seen in lesions.

The reduced NAA in MS CGM and NAWM suggest that mild but widespread Neuronal dysfunction or loss occurs early in the course of Relapsing/Remitting MS.

This preliminary finding should be confirmed in a larger cohort, and follow-up studies are also needed to determine the prognostic and PathoPhysiological significance of these early changes.